JP2001335483A - Nilvadipine-containing pharmaceutical peparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a readily eluting nilvadipine-containing solid pharmaceutical preparation. SOLUTION: This nilvadipine-containing solid pharmaceutical preparation comprises a solid dispersion such as a solid solution comprising nilvadipine, crospovidone and methyl cellulose.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a solid dispersion containing nilvadipine and a solid preparation containing nilvadipine containing the same which is easily dissolved.

[0002]

2. Description of the Related Art Nilvadipine: 6-cyano-
5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl)
Isopropyl ester of -1,4-dihydropyridine-3-carboxylic acid) is a calcium-antagonizing cerebral circulation improving and hypotensive agent, and improves psychiatric symptoms based on essential hypertension, cerebral blood flow disorder, sequelae of cerebral infarction It is used as an oral agent for treatment. However, since this substance is poorly soluble in water, it has a drawback of low bioavailability upon oral administration, and various formulations have been proposed to overcome this drawback.

[0003] Japanese Patent Publication No. 4-12245 discloses an easily soluble solid preparation comprising a solid solution using nilvadipine and hydroxypropylmethylcellulose. Also,
Japanese Patent Application Laid-Open No. H5-262642 discloses a solid dispersion produced by kneading nilvadipine and a water-soluble polymer base (such as a cellulose derivative and polyvinylpyrrolidone) while heating them at a temperature at which both do not melt. I have. These preparations are said to have excellent dissolution properties of the active ingredient, but the dissolution properties are not always satisfactory, and there is a problem in stability such as the dissolution property from the preparation decreases after long-term storage. Was.

[0004]

An object of the present invention is to provide an easily dissolvable solid preparation containing nilvadipine, which is excellent in stability. The present inventors have conducted intensive studies to solve the above problems, and as a result, by mixing methylcellulose with a solid dispersion using nilvadipine and crospovidone, it is possible to achieve both high dissolution property of nilvadipine and stability of the preparation. I found what I could do.

That is, the present invention provides a solid dispersion containing nilvadipine, crospovidone and methylcellulose,
And a solid preparation containing nilvadipine containing the solid dispersion. The invention also provides the use of nilvadipine for the production of the above solid dispersion.

[0006]

DETAILED DESCRIPTION OF THE INVENTION Nilvadipine (6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-
Dihydropyridine-3-carboxylic acid isopropyl ester) is a known substance and is readily available to those skilled in the art.
As an active ingredient of the preparation of the present invention, an optically active form of nilvadipine may be used.

[0007] Crospovidone (Crospovidone: 1-ethenyl-2-pyrrolidinone homopolymer) is widely used as a pharmaceutical additive (excipient or disintegrant).
CL-M (BASF Japan), Polyplasdon XL, XL-10, INF
Commercial products such as -10 (ISP Japan) can be obtained. Methylcellulose is widely used as a pharmaceutical additive (stabilizer, lubricant, base, etc.)
Commercial products such as (Shin-Etsu Chemical Co., Ltd.), Methocel A (Dow Chemical Japan) and Marporose M (Matsumoto Yushi Seiyaku) are available. The blending amounts of crospovidone and methylcellulose with respect to nilvadipine are not particularly limited, and can be appropriately selected by those skilled in the art so as to achieve desired ease of dissolution and stability. For example, crospovidone can be used in an amount of 1 to 20 parts by weight, preferably 2 to 15 parts by weight, more preferably 4 to 10 parts by weight based on 1 part by weight of nilvadipine, and methyl cellulose is used in an amount of 1 part by weight of nilvadipine. Can be used in an amount of 1 to 20 parts by weight, preferably 2 to 15 parts by weight, more preferably 4 to 10 parts by weight.

[0008] The preparation of the present invention is a solid dispersion (solid dispersion).
ion). The solid dispersion contained in the preparation of the present invention is substantially monomolecular nilvadipine dispersed in crospovidone and methylcellulose in a solid state. The method for preparing the solid dispersion is not particularly limited, and examples thereof include a solvent method and a melting method (Chem. Pharm. Bull., 9, 866, 1).
961; Int. J. Pharm., 47, 51, 1988), mixed pulverization method (mechanochemical method: Japanese Patent Publication No. 54-29565, 58-781).
No. 1), thermal mechanochemical method (Japanese Unexamined Patent Publication No. 5-26264)
No. 2) or the like.
These methods are well known to those skilled in the art.

Further, it may be prepared as a solid solution or coprecipitate, which is a solid in which nilvadipine is completely dissolved in crospovidone and methylcellulose. In this specification, the term “solid dispersion” is used as a concept including a solid solution. The method for preparing solid dispersions and solid solutions is described in “Recent Formulation Techniques and Their Applications I” (ed. Pharmaceutical Journal, pp. 157-159, 1).
983), “Recent formulation technology and its application III” (ed. By Pharmaceutical Journalists, pp.50-53, 1986), International Journal
of Pharmaceutics, 159, pp. 85-93, 1997 and the like.

The preparation of the present invention may contain, if necessary, excipients usually used in the field of preparation (for example, crystalline cellulose,
Corn starch, D-mannitol, lactose, etc.),
Disintegrators (eg, low-substituted hydroxypropylcellulose, hydroxypropyl starch, sodium starch glycolate, etc.), lubricants (eg, magnesium stearate), coloring agents, flavoring agents, and the like can be appropriately compounded. And the amount is not particularly limited.

The preparation of the present invention can be prepared as a solid preparation for oral administration, for example, in the form of tablets, capsules, granules, fine granules and the like, and the preparation method is well known to those skilled in the art. . For example, tablets coated with a film by a conventional method using a coating agent such as hydroxypropylmethylcellulose or hydroxypropylcellulose are preferable.

[0012]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not limited to the following examples. Example 1 (Comparative Example) 1 g of nilvadipine was completely dissolved in 100 g of ethanol.
4 g of crospovidone (Kollidon CL, manufactured by BASF) was uniformly dispersed in the solution. Next, the solvent was distilled off with an evaporator, dried under reduced pressure, and sieved with an 83-mesh sieve to obtain a solid dispersion containing nilvadipine.

Example 2 (Comparative Example) 1 g of nilvadipine was completely dissolved in 100 g of ethanol.
Crospovidone (Kollidon CL-M, BASF) 4 g is added to the solution.
Was uniformly dispersed. Next, the solvent was distilled off with an evaporator, dried under reduced pressure, and sieved with an 83-mesh sieve to obtain a nilvadipine-containing solid dispersion.

Example 3 (Invention) 1 g of nilvadipine was completely dissolved in 100 g of ethanol.
Crospovidone (Kollidon CL-M, BASF) 4 g was added to the solution.
And methylcellulose (Metroze SM-15, manufactured by Shin-Etsu Chemical) 4
g was evenly dispersed. Next, the solvent was distilled off with an evaporator, dried under reduced pressure, and sieved with an 83-mesh sieve to obtain a solid dispersion containing nilvadipine.

Example 4 (Comparative Example) To 1.0 g of the solid dispersion obtained in Example 1 was added 0.8 g of powder of methyl cellulose (Metrouse SM-15, manufactured by Shin-Etsu Chemical Co., Ltd.) and mixed to produce a solid preparation.

Example 5 (Invention) The solid dispersion obtained in Example 3, lactose (Dilactose S, manufactured by Freund Corporation), crystalline cellulose (Avicel 302, manufactured by Asahi Kasei), low-substituted hydroxypropylcellulose (L-HP)
C (LH-11), manufactured by Shin-Etsu Chemical Co., Ltd.), and further added and mixed with magnesium stearate and tableted to obtain a tablet containing a solid dispersion of nilvadipine. Table 1 shows the prescription per tablet. The hardness of the obtained tablet was measured using a tablet physical property measurement device (TM3-3,
It was 72.7N (average of 5 tablets, CV = 4.71%) as measured by Kikusui Seisakusho.

[0017]

[Table 1]

Example 6 (Comparative Example) 1 g of nilvadipine was completely dissolved in 100 g of ethanol.
4 g of methylcellulose (Metrouse SM-15, manufactured by Shin-Etsu Chemical) was uniformly dispersed in the solution. Next, the solvent was distilled off with an evaporator, dried under reduced pressure, and sieved with an 83-mesh sieve to obtain a nilvadipine-containing solid dispersion.

Test Example 1: Dissolution test In order to confirm the dissolution of nilvadipine, a dissolution test was carried out using a paddle method at 50 rpm, a test solution: 900 mL of water (37 ± 0.5 ° C.), and a sample: equivalent to 10 mg of nilvadipine. did. In addition, only one tablet (equivalent to 4 mg of nilvadipine) of the sample of Example 5 was used.

Test Example 2: Stability test In order to confirm the stability over time of the solid dispersion of nilvadipine, the obtained solid dispersion was placed in a glass bottle and opened.
Carry out accelerated test at 40 ° C and 75% RH, and test the dissolution properties in Test Example 1
Was carried out in the same manner as described above. The results are shown in FIGS.

The solid dispersion of the present invention (Example 3) has a
The elution amount was hardly changed up to 60 minutes, and had extremely excellent elution characteristics. In addition, the dissolution characteristics were maintained even after the accelerated test for 2 weeks and 4 weeks, and had extremely excellent stability (FIG. 3). Tablets prepared from this solid dispersion were also very fast-dissolving (FIG. 5). On the other hand, crospovidone (large particle type:
In the case of the solid dispersion using only Kollidon-CL) (Example 1), the solubility in the supersaturated state could not be maintained for a long time, and the solubility decreased over time (FIG. 1). The solid dispersion using the crospovidone fine particle type (Kollidon-CL-M) (Example 2) was excellent in dissolution, but the dissolution over time and the dissolution after the accelerated test for 2 weeks and 4 weeks were reduced. It was remarkable (FIG. 2).

In the composition (Example 4) in which methylcellulose was mixed with the solid dispersion containing crospovidone, a decrease in dissolution after the accelerated test for 2 weeks and 4 weeks was observed (FIG. 4). Furthermore, the dispersibility of the solid dispersion obtained from methyl cellulose alone (Example 6) was inferior to that of the solid dispersion of the present invention (FIG. 6).

[0023]

According to the present invention, a stable nilvadipine-containing solid preparation having excellent dissolution properties can be produced4.

[Brief description of the drawings]

FIG. 1 shows a solid dispersion containing nilvadipine (Example 1:
FIG. 9 is a view showing the dissolution property immediately after preparation of Comparative Example).

FIG. 2: Solid dispersion containing nilvadipine (Example 2:
FIG. 7 is a view showing dissolution properties immediately after preparation of Comparative Example) (closed triangles), and after accelerated tests for 2 weeks and 4 weeks (open circles and open diamonds).

FIG. 3 shows a solid dispersion containing nilvadipine (Example 3:
FIG. 3 is a view showing the dissolution properties immediately after preparation of the present invention) (closed triangles), after accelerated tests for 2 weeks and 4 weeks (open circles and open diamonds).

FIG. 4: Immediately after preparation of a solid preparation (Example 4: Comparative Example) in which methylcellulose is mixed with the solid dispersion containing nilvadipine obtained in Example 1 (Comparative Example) (solid triangles), 2 weeks, and 4 weeks
It is the figure which showed the dissolution property after a weekly accelerated test (open circles and open diamonds).

FIG. 5 is a graph showing the dissolution properties of tablets prepared from the solid dispersion containing nilvadipine obtained in Example 3 (invention) immediately after preparation.

FIG. 6: Immediately after preparation of a solid dispersion containing nilvadipine prepared using only methylcellulose (Example 6: Comparative Example) (closed triangles), after accelerated tests for 2 weeks and 4 weeks (open circles and open diamonds) FIG. 3 is a view showing elution properties.

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Claims (4)

[Claims] 1. A solid dispersion comprising nilvadipine, crospovidone, and methylcellulose. 2. The solid dispersion according to claim 1, which is a solid solution. 3. A solid preparation containing nilvadipine, comprising the solid dispersion according to claim 1 or 2. 4. The nilvadipine-containing solid preparation according to claim 3, which is in the form of a tablet.